Method and composition for treating alzheimer-type dementia

ABSTRACT

There is described a method for increasing the maximal tolerated close and thus the efficacy of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia by decreasing concomitant adverse effects by administration of said AChEI in combination with a non-anticholinergic antiemetic agent, whereby an enhanced acetyl choline esterase inhibition in the CNS of said patient is achieved and alleviation of the symptoms of Alzheimer type dementia in said patient is thereby improved to a greater extent. The use of a non-anticholinergic antiemetic agent for the preparation of a pharmaceutical composition for the treatment of Alzheimer type dementia in combination with an acetyl choline esterase inhibitor (AChEI) and pharmaceutical compositions comprising (a) a 5HT 3  receptor antagonist, a dopamine antagonist, a H1-receptor antagonist, a cannabinoid agonist, aprepitant or casopitant as an antiemetic agent and (b) an acetylcholine esterase inhibitor are also described.

This application claims the benefit of provisional application Ser. No.61/272,382 filed Sep. 18, 2009, the entire content of which is herebyincorporated by reference in this application.

FIELD OF THE INVENTION

This invention concerns a method for enhancing the maximal efficacy andmaximal tolerated dose of an acetyl choline esterase inhibitor in apatient suffering from dementia of the Alzheimer type by combining saidacetyl choline esterase inhibitor with an antiemetic agent, or the useof an antiemetic agent substantially devoid of central anticholinergicactivity for the preparation of pharmaceutical compositions for thetreatment of Alzheimer type dementias in combination with an acetylcholine esterase inhibitor (AChEI). The invention also concernspharmaceutical compositions comprising an antiemetic agent, inparticular a serotonin 5HT₃ receptor antagonist compound in associationwith an acetylcholine esterase inhibitor to allow increasing andprolonging efficacy and decreasing toxicity of these conventionalcholinomimetic treatments such as treatments for dementias in diseasesof the Alzheimer type.

DEFINITIONS

“AChEI(s)”: Acetyl Choline Esterase Inhibitor(s).

“CNS”: Central Nervous System.

“PNS”: Peripheral Nervous System.

“IR”: Immediate Release of the active ingredient from a composition.

“ER”: Extended Release of the active ingredient from a composition.

“Non-anticholinergic” refers to antiemetic medications not primarilyregarded as anticholinergic agents; they are entirely devoid ofanticholinergic activity or have an extremely low ability to preventacetylcholine from acting at its cholinergic receptor sites.

BACKGROUND OF THE INVENTION

Dementias of the Alzheimer type include, but are not limited toAlzheimer's disease, Parkinson's disease dementia, and related maladiesin humans involving cognitive and behavioral dysfunction such as Lewybody dementia. Most are chronic neurodegenerative disorders of the humancentral nervous system (CNS) characterized by progressive cognitiveimpairment, a variety of neurobehavioral and/or neuropsychiatricdisturbances, and restrictions in activities of daily living.

Alzheimer's disease is the most common form of dementia. Prevalencestudies indicated that in 2000 there were about 25 million persons withAlzheimer's disease worldwide and this number is expected to increase to114 million by 2050 unless an effective preventive or neuroprotectivetherapy emerges. Onset usually occurs in those over age 65. Clinicalsigns include progressive cognitive loss and other associatedneurobehavioral disabilities together with a declining capability ofperforming the activities of daily living.

The basic cause of sporadic Alzheimer's disease is not known, probablybecause the disease is heterogeneous and involves age-related changestogether with a complex interaction of genetic and environmental riskfactors. Current hypotheses advanced to explain the pathophysiology ofAlzheimer's disease center on the putative deleterious effects of thetwo misfolded and aggregated proteins, extracellular beta amyloid andintracellular tau. Presumably, as a consequence of the selectiveneurodegenerative process, the synthesis of the neurotransmitteracetylcholine declines. This reduction undoubtedly interferes withnormal synaptic transmission in brain. Drugs that act to correct theacetylcholine deficiency thus constitute the mainstay of currenttherapy.

Dementias of the Alzheimer type also include cognitive impairmentsassociated with Parkinson's disease. One example is Parkinson's diseasedementia, also a chronic progressive CNS degenerative disorder withrelatively late life onset. Parkinson's disease itself primarily affectsmotor function. But secondary symptoms include cognitive deterioration,especially deficits in executive function.

Another dementia of the Alzheimer type that is commonly linked toParkinson's disease is known as dementia with Lewy bodies or Lewy bodydementia. Although Lewy body dementia is now generally regarded as aseparate disease, differentiation from Alzheimer's disease and fromParkinson's disease dementia may be clinically challenging. Lewy bodydementia thus tends to be under-diagnosed or misdiagnosed as Alzheimer'sdisease or Parkinson's disease dementia. The clinical presentation ofLewy body dementia is typically one of cortical and subcorticalcognitive impairment, with visuospatial and executive dysfunction morepronounced than in Alzheimer's disease. Core clinical features of Lewybody dementia, in addition to parkinsonism, are cognitive decline plusfluctuations in attention and recurrent visual hallucinations.

Both Parkinson's disease dementia and Lewy body dementia arecharacterized neuropathologically by the presence of cortical Lewy bodypathology and synuclein protein deposition. Genetic factors appear toplay a role in pathogenesis. Not surprisingly, the pathology ofParkinson's disease dementia and Lewy body dementia is heterogeneous andoverlapping, often intermixed with changes of the Alzheimer and vasculartypes. A reduction in brain acetylcholine-mediated neurotransmission hasbeen linked to the primary clinical abnormalities found in both thesedisorders and drugs acting to stimulate cholinergic transmission nowconstitute the main approach to therapy.

In addition to the aforementioned disorders, the off labeladministration of drugs that augment CNS cholinergic transmission forvarious other cognitive disorders is widespread. Some of this useinvolves cognitive disorders for which relatively little clear evidenceof cholinergic dysfunction currently exists. Nevertheless, an increasingnumber of clinical studies now support a rational extension of AChEItreatment to various additional disorders of cognitive function,including but not limited to, vascular dementia, Down syndrome,traumatic brain injury and mild cognitive impairment.

As noted above, reduced levels of neurotransmitters includingacetylcholine have been reported in dementias of the Alzheimer type andrelated disorders. In particular, a deficit in acetylcholine-mediatedtransmission is thought to contribute to the cognitive and certain ofthe neurobehavioral abnormalities associated with these disorders.Accordingly, drugs known to augment cholinergic transmission in the CNSare widely used in therapy.

AChEIs are now part of the standard care for patients suffering from adementia of the Alzheimer type and are widely used off label for variousother chronic progressive disorders of cognitive function. AChEIs havethe enhancement of acetylcholine-mediated neurotransmission as a generalmechanism of action. All act in the human CNS to increase and prolongthe availability of acetylcholine by inhibiting its degradatory enzymeacetylcholinesterase. Four AChEIs have been approved by the U.S. FDA forthe treatment of Alzheimer's disease and for Parkinson's diseasedementia: tacrine, donepezil [Aricept®], rivastigmine [Exelon®] andgalantamine [Razadyne®]. AChEIs are available in various formulationsincluding immediate release forms such as tablets, capsules andsolutions as well as rapid dissolving and extended release forms fororal administration as well as those for parenteral (e.g. transdermal)administration.

Other AChEIs, in particular tacrine analogs, such as ipidacrine;phenserine and their analogs; icopezil; and zanapezil are underevaluation.

Augmentation of cholinergic transmission in the CNS by currentlyavailable AChEIs confers therapeutic benefit to patients with Alzheimertype dementias. Therapeutic efficacy can be measured by the degree ofimprovement in cognitive dysfunction and other neurobehavioralabnormalities associated with these disorders using standardized scales.

Unfortunately, however, none of the currently available cholinomimeticor medications offer more than modest clinical benefit for some patientssuffering from any of the aforementioned dementing disorders, even whenthese medications are administered at their maximum safe and tolerateddoses. This is the first problem limiting the success of current AChEItherapy of Alzheimer type dementias.

Carefully conducted clinical trials of donepezil (Rogers et al.,Neurology 1998, 50, 136-45; Winblad et al. Neurology. 2001 Aug. 14;57(3):489-95), rivastigmine (Rosier et al., Brit. Med. J. 1999, 318,633-38; Farlow et al. Eur. Neurol., 2000, 44, 236-41) and galantamine(Raskind et al., Neurology, 2000, 54, 2261-68; Tariot et al., Neurology,2000, 54, 2269-76) in patients with dementias of the Alzheimer typedemonstrated small, but statistically significant, benefits on cognitiveand global measures relevant to dementia. The magnitude of the effect inpivotal clinical trials was on the order of a 2.8 point improvement onthe 70-point cognitive subscale of the Alzheimer's Disease AssessmentScale (ADAS-Cog), or 1-1.5 point improvement on the 30-point Mini-MentalStatus Examination (MMSE) compared to placebo over six months.Differences in global measures assessed by the 7-point ClinicianInterview-Based Impression of Change scale (CIBIC) were on the order of0.3-0.5 points in patients receiving an AChEI compared to thosereceiving placebo. Efficacy was similar for the three commonly usedAChEIs. AChEIs also appear to have a beneficial effect on the behavioraland neuropsychiatric symptoms in patients with Alzheimer type dementias.

A second problem limiting the success of current AChEI therapy ofAlzheimer type dementias is that, even at recommended amounts, all thesedrugs produce dose limiting adverse reactions. These side effectscommonly include, for the aforementioned AChEIs tacrine, donepezil,rivastigmine and galantamine: anorexia, nausea, vomiting, diarrhea,abdominal pain and weight loss (Physicians Desk Reference 2008, ThomsonP D R, Montvale, N.J.).

The most frequently reported adverse effects of rivastigmine, forexample, are gastrointestinal, especially nausea. About half of patientswho take this drug in the recommended therapeutic oral dose range of6-12 mg/day become nauseated and about one-third vomit at least once.Vomiting was severe in 2% of rivastigmine-treated patients and was mildor moderate in 14%. Five percent of patients discontinued rivastigminebecause of vomiting, compared to less than 1% on placebo. A loss ofappetite was reported by 17% of patients, and weight declined in 25%during rivastigmine therapy (averaging 7 to 10 pounds). Presumably, thedrug-induced anorexia, nausea and vomiting contribute to the observedweight loss. These untoward gastrointestinal effects, as well as othersoccurring with AChEI treatment, make it difficult to increaserivastigmine dosage above 6 mg daily in most patients.

Adverse events significantly reduce the safety and tolerability of AChEItherapy. Attempts to limit them in clinical practice now rely oninitiating treatment with a low dose and then escalating the doseslowly. Nevertheless, in current clinical practice, AChEI dosage isguided mainly by side effects and not by therapeutic effects in contrastto most drugs used in the treatment of neuropsychiatric disease. Theadministration of higher doses than recommended doses tends to increasethe frequency and severity of these side effects as well as introduceadditional kinds of adverse reactions. These include those generallyfound with high dose administration of cholinomimetics. In view of thefrequency and potential severity of these high dose adverse effects,maximum recommended oral doses of AChEIs are rarely intentionallyexceeded in clinical practice.

It is reported that recommended maximal dose levels of these drugstypically achieve only about 45% acetyl cholinesterase inhibition in theCNS of Alzheimer disease patients (Brannan S et al. ACNP 46^(th) AnnualMeeting, Program No. 4. Boca Raton Fla., Dec. 10, 2007—“Brannan 2007”)and that inhibition of acetyl cholinesterase activity and cognitiveimprovement are significantly correlated (Giacobini et al. J NeuralTransm. 2002 July; 109(7-8):1053-65) and that, ordinarily, a higherdegree of enzyme blockade must be attained for maximum functional effect(Jann et al., Clin Pharmacokinet. 2002; 41(10):719-39—“Jann 2002”).

On the other hand, doubling the dose of rivastigmine, which becameclinically practical when AChEI administration by immediate releasetablets was replaced by skin patches, which diminished side effects byblunting peak blood levels, significantly increased the amount ofcognitive improvement in patients with Alzheimer's disease withoutincreasing side effects.

By virtue of being dose limiting, these adverse effects also constrainthe efficacy of AChEI therapy. Studies in animal models of humancognitive dysfunction indicate a direct dose-response relation betweenthe amount of acetyl choline esterase inhibition and the degree ofcognitive improvement (Bennett B M et al., Neuropsychopharmacology. 2007March; 32(3):505-13). Similar conclusions have been drawn regardingAChEI effects on cognitive and behavioral symptoms in human patientswith Alzheimer's disease (Jann 2002; Winblad B, Cummings J, Andreasen N,Grossberg G, Onofrj M, Sadowsky C, Zechner S, Nagel J, Lane R. Int JGeriatr Psychiatry. 2007 May; 22(5):456-67).

The precise causes of the vomiting and related gastrointestinal symptomsinduced by AChEI therapy are not known. Presumably, they reflect thecholinergic receptor hyperstimulation attending AChEI administration.Vomiting is coordinated in a center located at the base of the brain.The vomiting center communicates with the nearby chemoreceptor triggerzone, whose stimulation can lead to such complaints of gastrointestinaldistress as anorexia, nausea and vomiting. The chemoreceptor triggerzone, which contains numerous serotonin 5-HT3 and dopamine D2 receptorsas well as those for acetylcholine, opioids and substance P, liesoutside the blood-brain barrier. Systemically administered antiemeticsacting at these or related transmitter receptor sites can thus inhibitvomiting even if unable to enter the CNS.

PRIOR ART

A benefit of alleviating the side effects of an AChEI was described in areport of four patients in whom the treatment of Alzheimer's diseasewith the AChEI tacrine was complicated by peripheral cholinergicgastrointestinal side effects, especially cramping, nausea, vomiting anddiarrhea (Faber et al. Am J Psychiatry 156:1, 1999, page 156—“Faber1999”). These adverse events were ameliorated by the adjunctive use ofthe anticholinergic propantheline (Pro-Banthine) at 7.5 mg to 15 mgtaken four times a day. Based on these results, the authors recommendedadjunctive use of propantheline in patients with untowardgastrointestinal cholinergic effects from cholinesterase inhibitors.

Several reports of benefiting these GI adverse effects with knownantiemetics have been published. For example, (See for example Jhee S S,Clin Neuropharmacol. 2002 March-April; 25(2):122-3, “Centrally actingantiemetics mitigate nausea and vomiting in patients with Alzheimer'sdisease who receive rivastigmine”; and Scarzella L, Funct Neurol. 2007April-June; 22(2):101-4.

Nevertheless, the aforementioned application of the general concept forimproving the treatment of dementias of the Alzheimer type provides onlylimited benefit to patients suffering from these disorders. Whilepotentially lessening side effects, merely employing the concomitant useof antiemetics such as propantheline and domperidone and others fallshort of realizing the full therapeutic potential of thisacetylcholinesterase approach to the treatment of Alzheimer typedementia. There are several major problems regarding the anticholinergicselected for use by Faber et al.: (1) the duration of action of theantiemetic was too short for current practical use in highlynon-compliant demented patients; and (2) none of these reports discloseor suggest that, by reducing adverse events, especiallygastrointestinal, it might be possible to increase AChEI dose and thusimprove efficacy.

These papers neither mention nor suggest using an antiemetic primarilyto raise the AChEI dose and thus improve antidementia efficacy.

In summary, the literature neither discloses nor suggests to takeadvantage of the side effect mitigation discovered by Faber 1999,achieved with propantheline, or of the nausea/vomiting side effectmitigations achieved with antiemetics to improve the magnitude and/orduration of the otherwise marginal therapeutic response to an AChEI, byallowing to increase the doses of said AChEI and concurrently improvingneurobehavioral function and quality of life. No attempt was made inthis direction heretofore.

SUMMARY OF THE INVENTION

Considering the results of the above-cited previously published studiesin animal models of human cognitive function indicating a dose-responserelation between the amount of AChEIs and the degree of cognitiveimprovement achieved in the clinically relevant dose range, it has beenassumed that if dose limiting side effects of AChEIs could be reduced oreliminated, then the administration of higher doses might provide a muchneeded increase in the size of the therapeutic effect and prolong theduration of drug action, while at the same time having no significantdeleterious effect on safety or tolerability.

The therapeutic approach according to the present invention reverses theapproach taught by the prior art, in the sense that it provides for anincrease of the therapeutic effect of the AChEI (i.e., increase inefficacy) by concurrently globally counteracting their side effects asopposed to combating their side effects without appreciably lesseningthe central activity of AChEIs, but without increasing their efficacy astaught by the whole prior art.

Thus, it has been found that it is actually possible to maximize theeffects of an AChEI in improving the symptoms of Alzheimer type dementiain a patient suffering from said symptoms by administering to saidpatient said AChEI in combination with a non-anticholinergic antiemeticagent as defined above. For the purposes of this definition, anon-anticholinergic antiemetic drug would have the degree ofacetylcholine blockade and the ability to influence the clinical effectsof cholinergic receptor stimulation of less than 20 percent of that ofatropine and preferably less than 5 percent of that of atropine.

It has also surprisingly been found that by a combined antiemetic/AChEItreatment, the maximization of the cholinomimetic efficacy is achievedwith AChEI doses higher than the currently maximal tolerated ones andwith antiemetic doses equal to or even lower than those currently usedfor preventing vomiting.

Finally, it has been found that pharmaceutical compositions comprising apharmacologically active amount of an AChEI and a pharmacologicallyactive amount of a non-anticholinergic antiemetic agent, in admixturewith pharmaceutical carriers, improve the symptoms of Alzheimer typedementia in patients suffering from said symptoms, even in the case ofpatients who have been withdrawn or are no longer responding to theAChEI therapy because of the severe side-effects, thus assuring not onlyan improvement of the quality of life of the patients, but also anobjective and previously unrealized improvement of their symptoms.

DETAILED DESCRIPTION

The present invention proposes an improved method to augment theefficacy of conventional cholinergic therapies for Alzheimer typedementias by mitigating the common adverse events of cholinomimetictreatments of said Alzheimer type dementias that arise as a result ofthe concomitant stimulation of cholinergic receptors mediating emesisand emesis-related symptoms at the central vomiting center andchemoreceptor trigger zone as well as at peripheral sites.Non-anticholinergic antiemetic drugs that act to inhibit thenausea/vomiting side effects resulting from cholinomimetic therapy havethe potential to reduce the adverse effects, such that highercholinomimetic doses can be administered leading to higher and moreprolonged antidementia efficacy. By combining an extended releasecholinomimetic with a non-anticholinergic antiemetic having anadvantageous duration of pharmacologic action, in a single dosage form,the benefits to patients of an even longer duration of action is alsoachieved.

Thus, it is an object of the present invention to provide a method forenhancing the maximal tolerated dose of an acetyl choline esteraseinhibitor in a patient suffering from an Alzheimer type dementia withoutconcurrent, appreciable adverse effects, which comprises administeringto said patient said AChEI in combination with a non-anticholinergicantiemetic agent, whereby an enhanced acetyl choline esterase inhibitionin the CNS of said patient is achieved and the symptoms of an Alzheimertype dementia in said patient are improved.

The invention also provides the use of a non-anticholinergic antiemeticagent for the preparation of pharmaceutical compositions for thetreatment of Alzheimer type dementias in combination with an AChEI,whereby the maximal tolerated dose of said AChEI is enhanced, a higherdegree of acetyl choline esterase inhibition in the CNS is achieved andthe symptoms of Alzheimer type dementia are improved to a greaterextent.

The efficacy of non-anticholinergic antiemetic agents in improving thesymptoms of Alzheimer type dementia is due to the fact that saidantiemetics allow the increase of the therapeutic doses of all theAChEIs up to a factor of 4.

Said AChEIs are those currently used or tested for this indication, suchas 1,2,3,4-tetrahydro-9-acridinamine (tacrine),9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine);(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and its pharmaceutically acceptable salts, in particular thehydrochloride,3-[2-(1-benzyl-4-piperidypethyl]-5,7,-dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one(icopezil) and its pharmaceutically acceptable salts, in particular themaleate,3-[1-benzylpiperidin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)propan-1-one(zanapezil) and its pharmaceutically acceptable salts, in particular thefumarate, (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenylcarbamate (rivastigmine) and its pharmaceutically acceptable salts, inparticular the hydrogen (2R,3R)-tartrate,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and its pharmaceutically acceptable salts;(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(huperzine A) and phenserine and its analogs encompassed by the generalformula I

wherein Q is a phenyl group optionally substituted with a (C₁-C₄)alkylor with a methoxy group, Z is an oxygen or sulfur atom or a N-E′radical, E and E′, independently, are hydrogen or a methyl groupoptionally substituted with a phenyl or benzyl group.

Exemplary AChEIs of formula (I), described in U.S. Pat. No. 6,683,105,are phenserine (Q=phenyl; E=CH₃; Z=N—CH₃); (−)-N¹,N⁸-bisnorphenserine(Q=phenyl; E=H; Z=N—H); 4′-methoxyphenserine (Q=4′-methoxyphenyl; E=CH₃;Z=N—CH₃); (−)-N¹,N⁸-bisbenzylnorphenserine (Q=phenyl; E=CH₂C₆H₅;Z=N—CH₂C₆H₅); tolserine (Q=o-tolyl; E=CH₃; Z=N—CH₃);N¹-benzylnortolserine (Q=o-tolyl; E=CH₃; Z=N—CH₂—C₆H₅);N¹-phenethylnortolserine (Q=o-tolyl; E=CH₃; Z=N—CH₂—CH₂—C₆H₅);N¹-nortolserine (Q=o-tolyl; E=CH₃; Z=N—H); N⁸-benzylnortolserine(Q=o-tolyl; E=N—CH₂—C₆H₅; Z=N—CH₃); N⁸-phenethylnortolserine (Q=o-tolyl;E=N—CH₂—CH₂—C₆H₅; Z=N—CH₃); N⁸-nortolserine (Q=o-tolyl; E=H; Z=N—CH₃);N¹,N⁸-bisnortolserine (Q=o-tolyl; E=H; Z=N—H);(−)-N¹,N⁸-bisbenzylnortolserine (Q=o-tolyl; E=CH₂C₆H₅; Z=N—CH₂C₆H₅);cymserine (Q=p-isopropylphenyl; E=CH₃; Z=N—CH₃); N¹-benzylnorcymserine(Q=p-isopropylphenyl; E=CH₃; Z=N—CH₂—C₆H₅); N¹-phenethylnorcymserine(Q=p-isopropylphenyl; E=CH₃; Z=N—CH₂—CH₂—C₆H₅); N¹-norcymserine(Q=p-isopropylphenyl; E=CH₃; Z=N—H); N⁸-benzylnorcymserine(Q=p-isopropylphenyl; E=N—CH₂—C₆H₅; Z=N—CH₃); N⁸-phenethylnorcymserine(Q=p-isopropylphenyl; E=N—CH₂CH₂C₆H₅; Z=NCH₃); N⁸-norcymserine(Q=p-isopropylphenyl; E=H; Z=N—CH₃); N¹,N⁸-bisnorcymserine(Q=p-isopropylphenyl; E=H; Z=N—H); (−)—N¹,N⁸-bisbenzylnorcymserine(Q=p-isopropylphenyl; E=CH₂C₆H₅; Z=N—CH₂C₆H₅); thiacymserine(Q=p-isopropylphenyl; E=CH₃; Z=S); thiatolserine (Q=o-tolyl; E=CH₃;Z=S).

Donepezil hydrochloride, rivastigmine hydrogen (2R,3R)-tartrate andgalantamine hydrobromide are the most used AChEIs.

Any antiemetic agent substantially devoid of central anticholinergiceffects may be used according to the present invention to improve theefficacy of the AChEIs by allowing an effective increase of theirtherapeutic doses.

Typical non-anticholinergic antiemetic agents are

-   -   5-HT₃ receptor antagonists (5HT3-antagonists), such as        9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydrocarbazol-4-one        (ondansetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride dihydrate, described in        EP 191562; 3S-ondansetron; 3R-onsdansetron;        (3R)-10-oxo-8-azatricyclo[5.3.1.0^(3,8)]undec-5-yl        1H-indole-3-carboxylate (dolasetron) and pharmaceutically        acceptable salts and solvates thereof, in particular its        monomethanesulfonate (mesylate or mesilate) monohydrate,        described in EP 266730;        1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-indazole-3-carboxamide        (granisetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in EP        200444;        [(1S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]1H-indole-3-carboxylate        (tropisetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its monohydrochloride, described in U.S.        Pat. No. 4,789,673;        1-phenylmethyl-2-piperazinyl-1H-benzimidazole (lerisetron) and        pharmaceutically acceptable salts and solvates thereof, in        particular its hydrochloride, described in EP 512939;        (R)-5-[(1-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole        (ramosetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in U.S. Pat.        No. 5,344,927;        (3aR)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one        (palonosetron) and pharmaceutically acceptable salts and        solvates thereof, in particular its hydrochloride, described in        U.S. Pat. No. 5,202,333;        2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one        (alosetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in U.S. Pat.        No. 5,360,800; and        (±)-6-chloro-,3,4-dihydro-4-methyl-3-oxo-N-(quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide        (azasetron) and pharmaceutically acceptable salts and solvates        thereof, in particular its hydrochloride, described in U.S. Pat.        No. 4,892,872; which are known to be serotonin receptors        blockers in the central nervous system and gastrointestinal        tract and have been proposed for use to treat post-operative and        cytotoxic drug nausea and vomiting;    -   dopamine antagonists (“DA-antagonists”), such as        5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one        (domperidone) and pharmaceutically acceptable salts and solvates        thereof, particularly its maleate;        1-[1-[4-(4-fluorophenyl)-4-oxo-butyl]-3,6-dihydro-2H-pyridin-4-yl]-3H-benzoimidazol-2-one        (droperidol);        4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one        (haloperidol);        3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine        (chlorpromazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;        2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine        (prochlorperazine), and pharmaceutically acceptable salts and        solvates thereof, particularly its dimaleate, dimesylate or        1,2-ethanedisulfonate (1:1) (edisilate);        dimethyl[1-(10H-phenothiazin-10-yl)propan-2-yl]amine        (promethazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;        4-aminosalicylamide and benzamide derivatives like        4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide        (metoclopramide) and pharmaceutically acceptable salts and        solvates thereof such as its monohydrochloride monohydrate;        4-amino-5-bromo-N-[2-(diethylamino)ethyl]-2-methoxybenzamide        (bromopride) and pharmaceutically acceptable salts and solvates        thereof, particularly its monohydrochloride and its        dihydrochloride monohydrate;        4-amino-N-(1-benzylpiperidin-4-yl)-5-chloro-2-methoxybenzamide        (clebopride) and pharmaceutically acceptable salts and solvates        thereof, particularly its malate or its hydrochloride        monohydrate;        N-[(1-allylpyrrolidin-2-yl)methyl]-6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxamide        (alizapride) and pharmaceutically acceptable salts and solvates        thereof, particularly its hydrochloride;        (L)-2-methoxy-N-(1-propylpyrrolidin-2-yl)methyl)-5-sulfamoylbenzamide        (levosulpiride);        N-{[4-(2-dimethylaminoethoxy)phenyl]methyl}-3,4,5-trimethoxy-benzamide        (trimethobenzamide) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride; which act in        the brain and especially at the chemoreceptor trigger zone and        are known to be used to treat nausea and vomiting associated        with neoplastic disease, radiation sickness, opioids, cytotoxic        drugs and general anesthetics;    -   H1 histamine receptor antagonists (“H1-antagonists”), such as        1-[(4-chlorophenyl)-phenyl-methyl]-4-[(3-methylphenyl)methyl]piperazine        (meclizine or meclozine) and pharmaceutically acceptable salts        and solvates thereof, particularly its dihydrochloride        monohydrate;        dimethyl[1-(10H-phenothiazin-10-yl)propan-2-yl]amine        (promethazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its hydrochloride;        3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine        (chlorpromazine) or a salt thereof, particularly its        hydrochloride;        2-chloro-10-[3-(4-methyl-1-piperazinyl)propyl]-10H-phenothiazine        (prochlorperazine) and pharmaceutically acceptable salts and        solvates thereof, particularly its dimaleate, dimesylate or        1,2-ethanedisulfonate (1:1) (edisilate); and        2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)ethanol        (hydroxyzine) and pharmaceutically acceptable salts and solvates        thereof such as its hydrochloride or        1,1′-methylene-bis(2-hydroxy-3-naphthalenecarboxylic acid salt        (pamoate), which are known to be effective in many conditions,        including motion sickness and severe morning sickness in        pregnancy;    -   cannabinoid receptor agonists (“cannabinoids”), such as        cannabis;        (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol        (dronabinol);        (6aR,10aR)-rel-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy,6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one        (nabilone); and        (−)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol        (CP 55,940); which are known to be used in patients with        cachexia and cytotoxic nausea and vomiting;    -   antagonists of the neurokinine 1 receptor (NK1-antagonists) such        as        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (aprepitant); and        (2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide        (casopitant); which are known to be neurokinine-1 receptors        blockers in both the central and peripheral nervous system and        have been proposed for use to treat cytotoxic drug nausea and        vomiting.

Advantageously, the used non-anticholinergic antiemetic agents arecompounds with a duration of action of at least 6 hours, advantageouslyfrom 8 to 24 hours, more advantageously from 10 to 24 hours, preferablyfrom 12 to 24 hours, even though non-anticholinergic antiemetics havingan appropriate duration of action corresponding to the duration ofaction of the concomitantly administered AChEI may be successfully used.

According to the present invention, the non-anticholinergic antiemeticagent is administered at doses of from 50% to 300% of the currentlyrecommended IR dose in its antiemetic indication, it being understoodthat doses of from 50% to 200% will be used in immediate release unitforms while doses of from 75% to 300% will be used in extended releaseor transdermally applicable unit forms. Such a dose will allow themaximization of the cholinomimetic efficacy with AChEI doses higher thanthe currently maximal tolerated ones, in particular with doses of AChEIsat least as high as the currently recommended doses and preferablyhigher than said currently recommended doses, in particular of 100% to300%, and preferably of 150% or 200% up to or 300% of said recommendeddose of AChEI to patients suffering of Alzheimer type dementia withoutclinically significant symptoms of gastrointestinal distress,particularly anorexia, nausea or vomiting.

According to an embodiment, the non-anticholinergic antiemetic agent tobe administered to patients under treatment with an AChEI is a5HT3-antagonist selected from the group consisting of alosetron andpharmaceutically acceptable salts and solvates thereof, at a daily dose(in alosetron) of from 0.25 mg to 6 mg; dolasetron and pharmaceuticallyacceptable salts and solvates thereof, at a daily dose (in dolasetron)of from 50 mg to 300 mg; granisetron and pharmaceutically acceptablesalts and solvates thereof, at a daily dose (in granisetron) of from 1mg to 6 mg; ondansetron and pharmaceutically acceptable salts andsolvates thereof, at a daily dose (in ondansetron) of from 12 mg to 72mg; and tropisetron and pharmaceutically acceptable salts and solvatesthereof, at a daily dose (in tropisetron) of from 2.5 mg to 15 mg.

According to another embodiment, the non-anticholinergic antiemeticagent to be administered to patients under treatment with an AChEI is adopamine antagonist selected from the group consisting of domperidoneand pharmaceutically acceptable salts and solvates thereof, at a dailydose (in domperidone) of from 15 mg to 90 mg; haloperidol, at a dailydose of from 0.25 mg to 60 mg; chlorpromazine and pharmaceuticallyacceptable salts and solvates thereof, at a daily dose (inchlorpromazine) of from 25 mg to 450 mg; prochlorperazine andpharmaceutically acceptable salts and solvates thereof, at a daily dose(in prochlorperazine) of from 7.5 mg to 120-150 mg; the4-aminosalicylamide derivatives metoclopramide and pharmaceuticallyacceptable salts and solvates thereof, at a daily dose (inmetoclopramide) of from 15 mg to 90 mg; bromopride, at a daily dose (inbromopride) of from 10 mg to 180 mg; clebopride and pharmaceuticallyacceptable salts and solvates thereof, at a daily dose (in clebopride)of from 0.75 mg to 4.5 mg; levosulpiride, at a daily dose of from 37.5mg to 900 mg; alizapride and pharmaceutically acceptable salts andsolvates thereof, at a daily dose (in alizapride) of from 25 mg to 600mg; and trimethobenzamide and pharmaceutically acceptable salts andsolvates thereof, at a daily dose (in trimethobenzamide) of from 450 mgto 3,600 mg.

According to another embodiment, the non-anticholinergic antiemeticagent to be administered to patients under treatment with an AChEI is aH1 histamine receptor antagonist selected from the group consisting ofmeclizine (also called meclozine) and pharmaceutically acceptable saltsand solvates thereof, at a daily dose (in meclizine) of from 12.5 mg to300 mg; and promethazine and pharmaceutically acceptable salts andsolvates thereof, at a daily dose (in promethazine) of from 12.5 mg to112.5 mg.

According to another embodiment, the non-anticholinergic antiemeticagent to be administered to patients under treatment with an AChEI is acannabinoid receptor agonist selected from the group consisting ofdronabinol, at a daily dose of from 1.25 mg to 60 mg and nabilone, at adaily dose of from 1 mg to 12 mg.

According to another embodiment, the non-anticholinergic agent havingantiemetic action to be administered to patients under treatment with anAChEI is a neurokinine 1 receptor antagonist selected from the groupconsisting of aprepitant, at a daily dose of from 40 mg to 375 mg; andcasopitant, at a daily dose of from 25 mg to 450 mg.

According to an advantageous embodiment of the present invention, thenon-anticholinergic agent having antiemetic action to be administered topatients under treatment with an AChEI is granisetron or apharmaceutically acceptable salt thereof in a transdermal devicedelivering from 2 mg/24 hours to 6 mg/24 hours of granisetron,manufactured according to known techniques, in particular as describedfor example in U.S. Pat. No. 6,562,363 or in WO 2006/028866.

The administration of the non-anticholinergic agent having antiemeticaction to a patient suffering from dementia of Alzheimer type allows thetreatment with the maximal recommended doses of an AChEI withoutclinically significant symptoms of gastrointestinal distress,particularly anorexia, nausea or vomiting and also allows the treatmentof said patients with doses higher than the recommended doses, forexample with from 1.1 times to 2-3 times the recommended doses, saiddoses being higher than the maximal AChEI tolerated dose when usedalone, thus significantly improving the symptoms of dementia in saidpatients.

The fact that non-anticholinergic antiemetic agents allow the increaseof the maximal tolerated, therapeutic doses of the AChEIs results from arandomized, controlled safety, tolerability, pharmacokinetic andpharmacodynamic study of an AChEI agent alone, such as donepezil,rivastigmine or galantamine, and with a non-anticholinergic antiemeticagent, such as ondansetron, meclizine, prometazine, domperidone,metoclopramide or aprepitant, in normal volunteers.

The protocol is that of a phase 1 study of ascending standard doses ofrivastigmine alone (as a representative AChEI), and with ascendingstandard doses of ondansetron (as a representative non-anticholinergicantiemetic agent) in normal volunteers, to determine the differencebetween the maximum tolerated dose of rivastigmine as monotherapy andthe maximum tolerated dose of rivastigmine coadministered withondansetron as the primary endpoint, the secondary ones being adverseevent profile and drug plasma levels.

Standard approved oral dosage forms of both rivastigminehydrogen-(2R,3R)-tartrate (simply named rivastigmine in the study) andondansetron monohydrochloride, dihydrate (simply named ondansetron inthe study) are used. The objective: to determine the maximum tolerateddose (MTD), safety and tolerability as well as the pharmacokinetic andpharmacodynamic profile of rivastigmine when administered alone at dailyoral doses ranging from 3 mg to 12 mg and together with ondansetron atdaily oral doses of up to 24 mg. MTD, for the purposes of this protocol,is defined as the dose of rivastigmine just preceding the one thatproduced frank vomiting, or intolerable retching, or that is consideredmedically inappropriate for readministration by the study principalinvestigator. The ability of any volunteer to withdraw from this studyor refuse any medication or procedure is reiterated on a continuingbasis.

The volunteers are males and females, who are considered in good generalhealth, aged 18 to 80 years inclusive. No concomitant medications areallowed.

The study will be a randomized, double-blind, placebo-controlled,cross-over and parallel groups, dose-ranging, non-therapeutic, studyconducted on volunteers at a single center. The volunteers are evaluatedunder blinded conditions following randomization to either Group A orGroup B.

During the entire study, oral doses of rivastigmine or rivastigmineplacebo and ondansetron or ondansetron placebo will be administeredsimultaneously once daily at about 8 AM for up to 10 days. All subjectswill be maintained fasting for the preceding 8 hours (nominallymidnight) and until 4 hours after drug administration (nominally noon).Daily doses of rivastigmine begin at 3 mg and range up to 12 mg inincrements of 3 mg as deemed medically appropriate. Daily dosingcontinues until a subject vomits, evidences intolerable retching,refuses further study medications, or the principal investigatorterminates further dosing for medical reasons. Daily doses ofondansetron are 24 mg, given once daily at the same time asrivastigmine. In the case of ondansetron intolerance, in the opinion ofthe principal investigator, the daily dose of ondansetron may be reducedto and maintained at 12 mg.

Volunteers who are randomized to Group A receive single daily doses ofrivastigmine starting at 3 mg per day and ascending by 3 mg incrementseach study day, as tolerated, to a maximum of 12 mg per day. Once theMTD (as defined above) for rivastigmine as monotherapy is determined,simultaneous ondansetron administration begins at a dose of 24 mg perday and continues each study day at this dose. One day after theintroduction of ondansetron, rivastigmine administration resumes at thepreviously determined MTD and rises each study day by increments of 3mg, as tolerated, to a maximum of 12 mg per day. The study terminatesfor each volunteer once they have reached their MTD for rivastigminewhen administered in combination with ondansetron.

Volunteers who are randomized to Group B first receive ondansetron givenonce daily at 12 mg and then increased on the second study day to andmaintained at 24 mg once daily, as tolerated. Then daily doses ofsimultaneously administered rivastigmine are introduced, starting at 3mg and rising in 3 mg increments each study day as tolerated to eachsubjects' MTD or 12 mg which ever occurs first.

During each study day all subjects receive a constant number of similarappearing rivastigmine or rivastigmine placebo capsules and ondansetronor ondansetron placebo tablets once daily. Both study subjects andCenter Staff receive no information concerning drug type or quantityadministered at any time during the study. Drugs are administered andcompliance assured by an attendant in accordance with orders from amedically qualified investigator. Neither will communicate with studysubjects nor those having contact with these subjects.

Drug dosing will be in accordance with the attached Dosing Schedule asconsidered medically appropriate by the principal investigator. Standardapproved oral dosage forms of both rivastigmine and ondansetron will beused. Placebo tablets (or capsules) will have a similar appearance tothe active drug tablets (or capsules). All drugs will be administeredorally, once daily in the morning at about 0800 hours. On study days,subjects will be kept fasting from 0000 hours (midnight) until at least4 hours after drug administration (about 1200 hours).

Safety and tolerability are evaluated before, during and after studydrug administration by means of reports from subjects as well as bymedical staff observations and measurements. Medical proceduresincluding clinical history and physical examination, vital signs andlaboratory tests are performed at screening, and at a follow up visitabout 7 days after the last drug administration. Some medical proceduresare in addition performed each study day.

During each study day, all subjects remain under continuous observationfrom just before drug administration until 4 hours after drugadministration, or until all medically significant study-relatedabnormalities have subsided. The following tests are performed duringeach study day: review of systems (focused on known adverse effects ofthe drugs used), and vital signs (sitting systolic and diastolic bloodpressure and radial pulse rate), just before drug dosing and 2 hoursthereafter or until any abnormalities have subsided. A 12-lead ECG isobtained on admission and again 2 hours after MTD rivastigmineadministration. Laboratory tests include urinalysis and routineevaluations of venous blood samples (including fasting blood sugar,blood urea nitrogen, creatinine, liver transaminases, alkalinephosphatase and bilirubin) on the first and last study days.

The following adverse events are monitored:

(a) Anorexia or nausea, rated daily by a blinded observer during thepeak dose period (1 to 2 hours after oral drug administration) inaccordance with responses from study subjects during the peak doseperiod (1 to 2 hours after drug administration) on a numeric scale of 0(absent) to 5 (very severe).

(b) Retching, rated daily as either absent or present during the peakdose period as witnessed by a blinded observer;

(c) Vomiting, rated daily as either absent or present during the peakdose period as witnessed by a blinded observer; and

(d) Others, rated once daily as either absent or present by a blindedobserver in accordance with responses from study subjects: diarrhea,abdominal pain, coughing or other respiratory difficulty, chest pain,palpitations, dysuria or other urinary disturbance, blurring of vision,light headedness, syncope, somnolence, agitation, confusion.

For the pharmacokinetic measurements, venous blood samples are collectedthree times from each subject: (1) at baseline just prior to the firstrivastigmine dose, (2) at rivastigmine peak dose 75 minutes after MTDadministration and (3) at 4 hours after MTD rivastigmine administration.All specimens are centrifuged, and the serum separated and stored frozenfor subsequent assay.

The analysis of primary outcome measure is performed both in studycompleters and in the intent-to-treat (ITT) population. The ITTpopulation will include all the randomized subjects who have receivedeach of the baseline assessments and at least one post-randomizationassessment.

Difference in the MTD of rivastigmine when given alone and together withondansetron is analyzed using descriptive statistics both withinsubjects and between subjects assigned to each of the two treatmentorder groups.

Safety parameters are analyzed to compare differences between therivastigmine monotherapy and the rivastigmine plus ondansetron treatmentgroups. These parameters include treatment-emergent adverse events,vital signs, routine laboratory determinations, and ECG measurements.

For the intended use, the non-anticholinergic antiemetic agent isformulated in pharmaceutical compositions comprising, as an activeingredient thereof, said non-anticholinergic antiemetic agent inadmixture with a pharmaceutical carrier.

Said composition may be formulated with said pharmaceutical carrier inIR or ER unit forms for oral administration or in unit forms forparenteral, i.e. intramuscular, intravenous, rectal or transdermal,administration.

The non-anticholinergic antiemetic agent is present in an amount thatreduces peripherally mediated gastrointestinal adverse effects thatwould be caused by the administration of a dose of AChEI sufficient tomaximally alleviate disease-associated dementia and otherneurobehavioral symptoms.

Advantageously, these pharmaceutical compositions comprise thenon-anticholinergic antiemetic active ingredient in an amount of from50% to 300% of the dosage used in the compositions currently used forthe treatment of disorders such as nausea, vomiting or motion sickness.The compositions prepared using the non-anticholinergic antiemeticagents according to the present invention allow the maximization of thecholinomimetic efficacy with AChEI doses higher than the currentlymaximal tolerated ones, in particular by administration of from 1.5 upto three times the recommended dose of AChEI, to patients suffering ofAlzheimer type dementia without clinically significant symptoms ofgastrointestinal distress particularly anorexia, nausea or vomiting,thus significantly improving the symptoms of dementia.

The compositions are preferably formulated in dosage unit forms for oralor parenteral, in particular transdermal, administration, wherein thenon-anticholinergic antiemetic active ingredient is mixed with apharmaceutical carrier.

The pharmaceutical compositions prepared using the non-anticholinergicantiemetic agents according to the present invention are indicated inthe treatment of the symptoms of Alzheimer type dementias in order toimprove to a greater extent said symptoms by also allowing an increaseof the currently used and also of the maximal tolerated doses of anAChEI, concurrently or sequentially administered therewith, without theside-effects that would hinder said increase of said therapeutic doses.

In said pharmaceutical compositions, the non-anticholinergic antiemeticagent is present in an amount of from 50% to 300% of the amount of saidnon-anticholinergic antiemetic agent contained in the currentlyadministered IR dosage unit forms for the treatment of disorders such asnausea, vomiting or motion sickness. More particularly, thenon-anticholinergic antiemetic agent is present, in an IR unit form, inan amount ranging from 50% to 200% of the amount of saidnon-anticholinergic antiemetic agent contained in the currentlyadministered IR dosage unit forms for the treatment of the above-citeddisorders or, in an ER unit form, in an amount ranging from 75% to 300%of the amount of said non-anticholinergic antiemetic agent contained inthe currently administered unit dosage IR forms for the treatment of theabove-cited disorders.

An advantageous non-anticholinergic antiemetic agent in saidpharmaceutical compositions is selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inan amount (in alosetron) of from 0.25 mg to 3 mg; dolasetron andpharmaceutically acceptable salts thereof, in an amount (in dolasetron)of from 25 mg to 300 mg; granisetron and pharmaceutically acceptablesalts thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg;ondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 2 mg to 24 mg; tropisetron andpharmaceutically acceptable salts thereof, in an amount (in tropisetron)of from 2.5 mg to 15 mg; domperidone and pharmaceutically acceptablesalts and solvates thereof, in an amount (in domperidone) of from 5 mgto 30 mg; haloperidol, in an amount of from 0.5 mg to 30 mg;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof, in an amount (in chlorpromazine) of from 12.5 mg to 300 mg;prochlorperazine and pharmaceutically acceptable salts and solvatesthereof, in an amount of from 2.5 mg to 30 mg; metoclopramide andpharmaceutically acceptable salts and solvates thereof, in an amount (inmetoclopramide) of from 5 mg to 30 mg; bromopride and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in bromopride) offrom 5 mg to 30 mg; clebopride and pharmaceutically acceptable saltsthereof, in an amount (in clebopride) of from 0.25 mg to 1.5 mg;levosulpiride, in an amount of from 12.5 mg to 300 mg; alizapride andpharmaceutically acceptable salts thereof, in an amount (in alizapride)of from 25 mg to 150 mg; trimethobenzamide and pharmaceuticallyacceptable salts and solvates thereof, in an amount (intrimethobenzamide) of from 150 mg to 900 mg; meclizine (also calledmeclozine) and pharmaceutically acceptable salts and solvates thereof,in an amount (in meclizine) of from 6.25 mg to 150 mg; promethazine andpharmaceutically acceptable salts thereof, in an amount (inpromethazine) of from 12.5 mg to 150 mg; dronabinol, in an amount offrom 1.25 mg to 30 mg; nabilone, in an amount of from 0.25 mg to 3 mg;aprepitant, in an amount of from 20 mg to 375 mg; and casopitant, in anamount of from 25 mg to 150 mg.

According to an advantageous embodiment, the pharmaceutical compositionsprepared by using the non-anticholinergic antiemetics according to thepresent invention are present in unit forms also containing other activeingredients, in particular an AChEI which acts as cholinergic agent inthe CNS to improve the symptoms of Alzheimer type dementia, in aquantity sufficient to maximally alleviate disease-associatedneurobehavioral symptoms, with a minimum of treatment-associated adverseeffects.

Thus, it is another object of the present invention to provide apharmaceutical unit form which comprises

(a) a non-anticholinergic antiemetic agent; and

(b) an AChEI

in admixture with a pharmaceutical carrier.

In the pharmaceutical unit form of the present invention, thenon-anticholinergic antiemetic agent Component (a), is present in anamount of from 50% to 300% of the amount of the said non-anticholinergicantiemetic agent contained as a sole active ingredient in the currentlyused brand or generic drugs.

According to a preferred embodiment, said Component (a) is anon-anticholinergic antiemetic agent selected from the group consistingof (a1) 5HT3-antagonists, (a2) DA-antagonists, (a3) H1-antagonists, (a4)cannabinoids, (a5) aprepitant and (a6) casopitant.

The pharmaceutical composition to improve the treatment of humandementias of the Alzheimer type according to the present invention maycomprise a mixture of a non-anticholinergic antiemetic agent, Component(a), and of an AChEI, Component (b), wherein Component (b) is present ina quantity sufficient to maximally alleviate disease-associatedneurobehavioral symptoms and wherein Component (a) is present in asecond quantity that reduces adverse effects that would be caused by theAChEI if administered without the accompanying non-anticholinergicantiemetic agent.

Said amount of Component (b) sufficient to maximally alleviatedisease-associated cognitive and other neurobehavioral symptoms is from1 time to 3 times, advantageously 1.5 times to 3 times, preferably 2-3times the maximal dose contained in the currently used brand or genericAChEIs.

As to Component (a), typical 5HT3-antagonist non-anticholinergicantiemetic agents (a1) are the compounds described in EP 191562, inparticular ondansetron and pharmaceutically acceptable salts andsolvates thereof; the compounds described in EP 200444, in particulargranisetron and pharmaceutically acceptable salts and solvates thereof;the compounds described in EP 266730, in particular dolasetron andpharmaceutically acceptable salts and solvates thereof; the compoundsdescribed in U.S. Pat. No. 4,789,673, in particular tropisetron andpharmaceutically acceptable salts and solvates thereof; and thecompounds described in EP 430190, in particular palonosetron andpharmaceutically acceptable salts and solvates thereof.

Typical DA-antagonists (a2) are domperidone and pharmaceuticallyacceptable salts and solvates thereof such as the maleate;chlorpromazine and pharmaceutically acceptable salts and solvatesthereof such as the hydrochloride; prochlorperazine and its salts andsolvates, particularly the dimaleate and the dimesylate; promethazineand pharmaceutically acceptable salts and solvates thereof such as thehydrochloride; and 4-aminosalicylamide derivatives such asmetoclopramide and pharmaceutically acceptable salts and solvatesthereof such as the hydrochloride monohydrate, bromopride andpharmaceutically acceptable salts and solvates thereof such as themonohydrochloride or the dihydrochloride monohydrate, alizapride andpharmaceutically acceptable salts and solvates thereof such as thehydrochloride, and clebopride and pharmaceutically acceptable salts andsolvates thereof such as the malate and the hydrochloride monohydrate.

Typical histamine H1 receptor antagonists (a3) are meclizine (meclozine)and pharmaceutically acceptable salts and solvates thereof such as thehydrochloride monohydrate; promethazine and pharmaceutically acceptablesalts and solvates thereof such as the hydrochloride; chlorpromazine andpharmaceutically acceptable salts and solvates thereof such as thehydrochloride, prochlorperazine and pharmaceutically acceptable saltsand solvates thereof such as the dimaleate, the dimesylate or the1,2-ethanedisulfonate (1:1) (edisilate); hydroxyzine andpharmaceutically acceptable salts and solvates thereof such as thedihydrochloride or the 1,1′-methylenebis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate) salt.

Typical cannabinoids (a4) are nabilone and dronabinol.

Each of said typical non-anticholinergic antiemetic agents is present inthe pharmaceutical composition, as Component (a), in an amount rangingfrom 50% of the minimum amount to 300% of the maximum amount of saidtypical non-anticholinergic antiemetic agent contained in thecorresponding, currently used generic or brand drug for its antiemeticindication in IR form.

Advantageous Component (a) is selected from the group consisting ofalosetron and pharmaceutically acceptable salts and solvates thereof, inparticular the hydrochloride, in an amount (in alosetron) of from 0.25mg to 3 mg; dolasetron and pharmaceutically acceptable salts andsolvates thereof, in particular the mesylate, in an amount (indolasetron) of from 25 mg to 300 mg; granisetron and pharmaceuticallyacceptable salts and solvates thereof, in particular the hydrochloride,in an amount (in granisetron) of from 0.5 mg to 3 mg; ondansetron andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrochloride dihydrate, in an amount (in ondansetron) of from 2 mgto 24 mg; tropisetron and pharmaceutically acceptable salts and solvatesthereof, in particular the hydrochloride, in an amount of from 2.5 mg to15 mg; domperidone and pharmaceutically acceptable salts and solvatesthereof, in an amount (in domperidone) of from 5 mg to 30 mg;haloperidol, in an amount of from 0.5 mg to 30 mg; chlorpromazine andpharmaceutically acceptable salts and solvates thereof, in particularthe hydrochloride, in an amount (in chlorpromazine) of from 12.5 mg to75 mg; prochlorperazine and pharmaceutically acceptable salts andsolvates thereof, in particular the dimaleate, in an amount (inprochlorperazine) of from 2.5 mg to 30 mg; metoclopramide andpharmaceutically acceptable salts and solvates thereof, in particularthe monohydrochloride monohydrate, in an amount (in metoclopramide) offrom 5 mg to 30 mg; bromopride and pharmaceutically acceptable salts andsolvates, in particular the monohydrochloride and the dihydrochloridemonohydrate, in an amount (in bromopride) of from 5 mg to 30 mg;clebopride and pharmaceutically acceptable salts and solvates thereof,in particular the hydrogen malate and the hydrochloride monohydrate, inan amount (in clebopride) of from 0.25 mg to 1.5 mg; levosulpiride, inan amount of from 12.5 mg to 300 mg; alizapride and pharmaceuticallyacceptable salts thereof, in particular the hydrochloride, in an amount(in alizapride) of from 25 mg to 150 mg; trimethobenzamide andpharmaceutically acceptable salts thereof such as the monohydrochloride,in an amount (in trimethobenzamide) of from 150 mg to 900 mg; meclizine(also called meclozine) and pharmaceutically acceptable salts andsolvates thereof, in an amount (in meclizine) of from 6.25 mg to 150 mg;promethazine and pharmaceutically acceptable salts and solvates thereof,in particular the hydrochloride, in an amount (in prometazine) of from12.5 mg to 150 mg; dronabinol in an amount of from 1.25 mg to 60 mg;nabilone, in an amount of from 1 mg to 12 mg; aprepitant, in an amountof from 20 mg to 375 mg; and casopitant, in an amount of from 25 mg to150 mg.

Preferred Component (a) is selected from the group consisting ofondansetron and pharmaceutically acceptable salts and solvates thereof,in an amount (in ondansetron) of from 2 mg to 24 mg; granisetron andpharmaceutically acceptable salts and solvates thereof, in an amount (ingranisetron) of from 0.5 mg to 3 mg; domperidone and pharmaceuticallyacceptable salts and solvates thereof, in an amount (in domperidone) offrom 5 mg to 30 mg; metoclopramide and pharmaceutically acceptable saltsand solvates thereof, in an amount (in metoclopramide) of from 5 mg to30 mg; dronabinol, in an amount of from 1.25 mg to 30 mg; nabilone, inan amount of from 0.25 mg to 3 mg; aprepitant, in an amount of from 20mg to 375 mg; and casopitant, in an amount of from 25 to 150 mg.

As to Component (b), typical AChEIs are1,2,3,4-tetrahydro-9-acridinamine (tacrine),9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine);(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one(donepezil) and its pharmaceutically acceptable salts,(S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate(rivastigmine) and its pharmaceutically acceptable salts,4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol(galantamine) and its pharmaceutically acceptable salts;(1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0^(2,7)]trideca-2(7),3,10-trien-5-one(huperzine A) and phenserine and its analogs encompassed by the generalformula I.

Advantageous AChEIs include those now part of standard care for patientssuffering from a dementia of the Alzheimer type and that are also widelyused off-label for various other chronic progressive disorders ofcognitive function. AChEIs have as a general mechanism of action theenhancement of acetylcholine-mediated neurotransmission. All act in thehuman CNS to increase and prolong the availability of acetylcholine byinhibiting its degradatory enzyme acetylcholinesterase, such as tacrine;huperzine A; donepezil; pharmaceutically acceptable salts of donepezil,especially the hydrochloride thereof; icopezil; pharmaceuticallyacceptable salts of icopezil, especially the maleate thereof; zanapezil;pharmaceutically acceptable salts of zanapezil, especially the fumaratethereof; rivastigmine; pharmaceutically acceptable salts ofrivastigmine, especially the hydrogen tartrate thereof; galantamine;pharmaceutically acceptable salts of galantamine especially thehydrobromide thereof.

Preferred Component (b) is an AChEI selected from the group consistingof tacrine; huperzine A; donepezil and pharmaceutically acceptable saltsthereof, in particular its hydrochloride; rivastigmine andpharmaceutically acceptable salts thereof, in particular itshydrogen-(2R,3R)-tartrate (rivastigmine tartrate); galantamine andpharmaceutically acceptable salts thereof, in particular itshydrobromide; the group consisting of the last three AChEIs and of theirpharmaceutically acceptable salts being particularly preferred. As setforth above, these AChEIs vary in their pharmacological profiles and intheir affinities for acetylcholinesterase and butyrylcholinesterase.

The dose of the Component (b) may vary according to intrinsicacetylcholine esterase inhibiting potency of said component.Advantageously, said dose is from 1.5-fold to more than twice higherthan the maximal one currently used when the same AChEI is alone.

In the unit forms of the present invention, for immediate release orextended release, the antiemetic Component (a) is present in an amountof from 50% to 300% of the amount of said antiemetic contained in thecurrently administered IR dosage unit forms for the treatment ofdisorders such as emesis or motion sickness and the AChEI Component (b)is present in an amount of from 100% to 300% of the amount of said AChEIcontained in the currently administered IR dosage unit forms for thetreatment of Alzheimer type dementia.

More particularly, the non-anticholinergic antiemetic is present, in anIR unit form, in an amount ranging from 50% to 200% of the maximumamount of said antiemetic agent contained in the currently administeredIR dosage unit forms for the treatment of the above-cited disorders or,in an ER unit form, in an amount ranging from 75% to 300% of thecurrently administered IR dosage unit forms for the treatment of theabove-cited disorders.

For example, among the advantageous non-anticholinergic antiemeticagents used as Component (a), ondansetron or a pharmaceuticallyacceptable salt or solvate thereof, in particular its hydrochloridedihydrate, is present in an amount (in ondansetron) of from 2 mg to 16mg per dosage unit in an IR unit form or in an amount of from 3 mg to 24mg, preferably from 8 mg to 24 mg, in an ER unit form; alosetron or apharmaceutically acceptable salt thereof, in particular itshydrochloride, is present in an amount (in alosetron) of from 0.25 mg to2 mg per dosage unit in an IR unit form or in an amount of from 0.375 mgto 3 mg, preferably from 1 mg to 3 mg, in an ER unit form; tropisetronor a pharmaceutically acceptable salt thereof, in particular itshydrochloride, is present in an amount (in tropisetron) of from 2.5 mgto 10 mg per dosage unit in an IR unit form or in an amount of from 3.75mg to 15 mg, preferably from 5 mg to 24 mg, in an ER unit form;granisetron or a pharmaceutically acceptable salt thereof, in particularits hydrochloride, is present in an amount (in granisetron) of from 0.5mg to 2 mg per dosage unit in an IR unit form or in an amount of from0.75 mg to 3 mg, preferably from 1 mg to 3 mg, in an ER unit form;dolasetron, or a pharmaceutically acceptable salt thereof, in particularits mesilate, is present in an amount (in dolasetron) of from 25 mg to200 mg per dosage unit in an IR unit form or in an amount of from 37.5mg to 300 mg, preferably from 100 mg to 300 mg, in an ER unit form;domperidone or a pharmaceutically acceptable salt thereof, in particularits maleate, is present in an amount (in domperidone) of from 5 mg to 20mg per dosage unit in an IR unit form or in an amount of from 7.5 mg to60 mg, preferably from 10 mg to 60 mg, in an ER unit form;metoclopramide or a pharmaceutically acceptable salt or solvate thereof,in particular its monohydrochloride monohydrate, is present in an amount(in metoclopramide) of from 5 mg to 20 mg per dosage unit in an IR unitform or in an amount of from 7.5 mg to 30 mg, preferably from 10.0 mg to30.0 mg, in an ER unit form; alizapride or a pharmaceutically acceptablesalt thereof, in particular its hydrochloride, is present in an amount(in alizapride) of from 25 mg to 100 mg per dosage unit in an IR unitform or in an amount of from 37.5 mg to 300 mg, preferably from 100 mgto 300 mg, in an ER unit form; meclizine or a pharmaceuticallyacceptable salt thereof, in particular its hydrochloride is present inan amount (in meclizine) of from 6.25 mg to 100 mg per dosage unit in anIR unit form or in an amount of from 37.5 mg to 150 mg, preferably from50 mg to 150 mg, in an ER unit form; chlorpromazine or apharmaceutically acceptable salt thereof, in particular itshydrochloride is present in an amount (in chlorpromazine) of from 12.5mg to 200 mg per dosage unit in an IR unit form or in an amount of from75 mg to 300 mg, preferably from 150 mg to 300 mg, in an ER unit form;prochlorperazine or a pharmaceutically acceptable salt thereof, inparticular its maleate is present in an amount (in prochlorperazine) offrom 6.25 mg to 100 mg per dosage unit in an IR unit form or in anamount of from 37.5 mg to 150 mg, preferably from 50 mg to 150 mg, in anER unit form; dronabinol is present in an amount of from 1.25 mg to 20mg per dosage unit in an IR unit form or in an amount of from 1.8 mg to60 mg, preferably from 2.5 mg to 60 mg, in an ER unit form; nabilone ispresent in an amount of from 0.25 mg to 2 mg per dosage unit in an IRunit form or in an amount of from 0.75 mg to 3 mg per dosage unit in anIR unit form; aprepitant is present in an amount of from 20 mg to 250 mgper dosage unit in an IR unit form or in an amount of from 30 mg to 750mg, preferably from 125 mg to 500 mg, in an ER unit form; and casopitantis present in an amount of from 25 mg to 150 mg per dosage unit in an IRunit form.

Preferred Component (a) is a non-anticholinergic antiemetic agentselected from the group consisting of ondansetron and pharmaceuticallyacceptable salt and solvated thereof, in an amount (in ondansetron) offrom 2 mg to 24 mg; granisetron and pharmaceutically acceptable salt andsolvates thereof, in an amount (in granisetron) of from 0.5 mg to 3 mg;domperidone and pharmaceutically acceptable salts and solvates thereof,in an amount (in domperidone) of from 5 mg to 30 mg; metoclopramide andpharmaceutically acceptable salts and solvates thereof, in an amount (inmetoclopramide) of from 5 mg to 30 mg; dronabinol, in an amount of from1.25 mg to 30 mg; nabilone, M an amount of from 0.25 mg to 3 mg;aprepitant, in an amount of from 20 mg to 375 mg; and casopitant, in anamount of from 25 mg to 150 mg.

In unit forms for immediate release or extended release, the AChEIComponent (b) is present in an amount of from 100% to 300% of the amountof said AChEI contained in the currently administered IR or ER dosageunit forms for the treatment of Alzheimer type dementia.

More particularly the AChEI Component (b) is present in an IR unit form,in an amount ranging from about 100% to about 300%, preferably from 150%to 300%, of the amount of said AChEI contained in the currentlyadministered IR dosage unit forms for the palliative treatment ofAlzheimer type dementia or, in an ER unit form, in an amount rangingfrom 150% to 300%, preferably from 200% to 300%, of the amount of saidAChEI contained in the currently administered unit dosage IR forms forthe treatment of Alzheimer type dementia.

For example, according to the present invention, among the preferredComponents (b), tacrine is present in amount of from 5 mg to 120 mg,advantageously from 40 mg to 120 mg, preferably from 60 mg to 120 mg perdosage unit; huperzine A is present in an amount of from 50 μg to 150μg, advantageously from 75 μg to 150 μg, preferably from 100 μg to 150μg per dosage unit; donepezil or a pharmaceutically acceptable saltthereof, preferably the hydrochloride, is present in an amount (indonepezil) of from 10 mg to 30 mg, preferably from 15 mg to 30 mg, perdosage unit; rivastigmine or a pharmaceutically acceptable salt thereof,preferably the hydrogen tartrate, is present in an amount (inrivastigmine) of from 6 mg to 18 mg, preferably from 9 mg to 18 mg perdose unit; and galantamine, or a pharmaceutically acceptable saltthereof, preferably the hydrobromide, is present in an amount (ingalantamine) of from 12 mg to 36 mg, preferably from 16 mg to 36 mg perdosage unit.

Advantageously, said AChEI can be administered in a dose that is higherthan the maximal tolerated dose of the same AChEI when administeredalone and will preferably be from 1.5 to 3 times higher than thecurrently recommended doses in the treatment of Alzheimer type dementia.

The unit form of the present invention may be a tablet, a capsule, apre-measured volume of a liquid solution or suspension for oraladministration or a patch for transdermal application. In said unit formthe antiemetic agent and the AChEI may be mixed together or separatedaccording to known technologies in admixture with a pharmaceuticalcarrier in a pharmaceutical composition.

Component (a) and Component (b) are formulated with conventionalpharmaceutical carriers in known formulations for oral use wherein saidcomponents are mixed together or separated, for example in two tabletsintroduced in a capsule or in a two-compartment capsule or in amultilayer (di-layer) tablet wherein the two components are both in IRor in ER form or one of the two components is in IR form and the otheris in ER form, according to known technologies.

The pharmaceutical carriers and vehicles are those commonly used for thepreparation of compositions for oral, buccal and parenteral, inparticular transdermal, administration. Appropriate unit forms comprisethe oral forms such as tablets, soft or hard gelatin capsules, powdersor granulates in sachets and suitably measured oral solutions orsuspensions as well as patches for transdermal administration.

Component (a) and Component (b) may also be present in form of one oftheir complexes with a cyclodextrin, for example α-cyclodextrin,β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin ormethyl-β-cyclodextrin.

Component (a) and Component (b) may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

For oral administration, Component (a) and Component (b), together orseparately, are formulated by mixing the active ingredient withconventional pharmaceutical acceptable carriers enabling said activeingredients to be formulated in tablets, dragees, orally disintegratingtablets, capsules, liquid solutions or suspensions, syrups and the like.

Carriers for IR tablets include for example starches, cellulose andderivatives thereof; lubricants such as talc, stearic acid or magnesiumstearate; diluents such as talc, powdered cellulose, lactose, starchessuch as maize or corn starch, mannitol, sorbitol; disaggregating agentssuch as microcrystalline cellulose or crospovidone; lubrifiants such aspolyethylenglycol or magnesium stearate; ligands such asmethylcellulose, sodium carboxymethylcellulose, alginic acid, alginates;sweeteners, such as saccharose, dextrose, mannitol, saccharin; orflavoring agents such as natural or synthetic oils.

Carriers for orally disintegrating tablets include for examplelubricants, aggregating, sweetening, flavoring or disaggregating agentsas well as agents improving the buccal mucosa absorption of Components(a) and (b) such as sorbitol, mannitol, lactose and cellulose.

Carriers for liquid, normally aqueous, suspensions or solutions includefor example antioxidants, such as sodium metabisulfite or sodiumsulfite, thickening agents, such as microcrystalline cellulose,hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone,preservatives such as methyl paraben, ethyl paraben, sodiumethylenediaminotetracetate, sodium benzoate or an alkaline salt ofsorbic acid, as well as flavoring and sweetening agents.

The sweeteners contained in the orally disintegrating tablets and theliquid suspensions or solutions may be natural, optional reduced sugarssuch as sucrose, dextrose, xylitol, mannitol or sorbitol, or syntheticproduct such as sodium saccharine or aspartame.

The flavoring agents are pharmaceutically acceptable flavors and tastesof synthetic and natural oils, the latter extracted from plants, leaves,flowers, fruits and their combinations, such as cinnamon, peppermint,anise and citron leaves, bitter almond, citrus fruits, in particularorange and/or lemon, linden and grapefruit oils. Also chocolate, vanillaor eucalyptus flavor and essences of fruit, in particular apple, pear,peach, strawberry, cherry, apricot, orange, lemon and grapes may beadvantageously used.

The composition according to the present invention may be in form of acapsule containing two tablets as described herein above, one of themcomprising Component (a) and the other comprising Component (b).

The association of a non-anticholinergic antiemetic and an AChEI may beformulated in tablets in which one or both of the two components is incontrolled-release formulation, for example as a dispersion of saidcomponent in hydroxypropyl methyl cellulose or in a film-coatedmicrogranule. Advantageously, the AChEI, in a ER-formulation is in thecore and the non-anticholinergic antiemetic agent, in IR-formulation, isin the outer layer in multi-layer tablets in which, for example, boththe core and the outer layer are coated with a film. Analogously,capsules made of two separated parts, one containing Component (a), inIR- or ER-formulation and the other containing Component (b), in IR- orER-formulation, may be used

Carriers and vehicles for ER tablets include retardant materials such asis acrylic and methacrylic acid polymers and copolymers; cellulosederivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylethylcellulose, hydroxypropylcellulose, methylcellulose,ethylcellulose, or sodium carboxymethylcellulose; gums; waxes;glycerides or aliphatic alcohols or a mixture thereof.

In particular, the unit forms of the present invention comprise

-   -   a non-anticholinergic antiemetic agent selected from the group        consisting of ondansetron and the pharmaceutically acceptable        salts and solvates thereof, in an amount (in ondansetron) of        from 2 mg to 24 mg; granisetron and the pharmaceutically        acceptable salts and solvates thereof, in an amount (in        granisetron) of from 0.5 mg to 3 mg; dolasetron and the        pharmaceutically acceptable salts and solvates thereof, in an        amount (in dolasetron) of from 25 mg to 300 mg; domperidone and        the pharmaceutically acceptable salts and solvates thereof, in        an amount (in domperidone) of from 5 mg to 30 mg; metoclopramide        and the pharmaceutically acceptable salts and solvates thereof,        in an amount (in metoclopramide) of from 5 mg to 30 mg;        alizapride and the pharmaceutically acceptable salts thereof, in        an amount (in alizapride) of from 25 mg to 150 mg; dronabinol,        in an amount of from 1.25 mg to 30 mg per dosage unit; nabilone,        in an amount of from 1 mg to 12 mg; aprepitant in an amount of        from 20 mg to 375 mg; and casopitant in an amount of from 25 mg        to 150 mg, as Component (a); and    -   a member selected from the group consisting of tacrine, in an        amount of from 10 mg to 120 mg, advantageously of from 40 mg to        120 mg preferably of from 60 mg to 120 mg; huperzine A, in an        amount of from 50 μg to 150 μg, advantageously of from 75 μg to        150 μg, preferably from 100 μg to 150 μg; donepezil and        pharmaceutically acceptable salts thereof, in an amount (in        donepezil) of from 5 mg to 30 mg, advantageously of from 10 mg        to 30 mg, preferably from 15 mg to 30 mg; rivastigmine and its        pharmaceutically acceptable salts, in an amount (in        rivastigmine) of from 1.5 mg to 18 mg advantageously of from 6        mg to 18 mg, preferably from 9 mg to 18 mg; and galantamine and        its pharmaceutically acceptable salts, in an amount, in        galantamine, of from 4 mg to 36 mg advantageously of from 12 mg        to 36 mg, preferably from 16 mg to 36 mg; as Component (b),        in admixture with a pharmaceutical carrier.

Preferred units forms comprise

-   (a) a non-anticholinergic antiemetic agent selected from the group    consisting of ondansetron and pharmaceutically acceptable salts and    solvates thereof, in an amount (in ondansetron) of from 2 mg to 16    mg; granisetron and pharmaceutically acceptable salts and solvates    thereof, in an amount (in granisetron) of from 0.5 mg to 2 mg;    domperidone and pharmaceutically acceptable salts and solvates    thereof, in an amount (in domperidone) of from 5 mg to 20 mg;    metoclopramide and pharmaceutically acceptable salts and solvates    thereof, in an amount (in metoclopramide) of from 5 mg to 20 mg;    dronabinol, in an amount of from 1.25 mg to 20 mg; nabilone, in an    amount of from 0.25 mg to 2 mg; aprepitant, in an amount of from 20    mg to 250 mg; and casopitant, in an amount of from 25 mg to 100 mg;    and-   (b) an AChEI selected from the group consisting of donepezil and    pharmaceutically acceptable salts thereof, in an amount (in    donepezil) of from 15 mg to 30 mg; rivastigmine and pharmaceutically    acceptable salts thereof, in an amount (in rivastigmine) of from 9    mg to 18 mg; and galantamine and pharmaceutically acceptable salts    thereof, in an amount (in galantamine) of from 16 mg to 36 mg;    in admixture with a pharmaceutical carrier.

Such unit forms, formulated as IR oral compositions, are particularlypreferred.

According to an embodiment, the compositions of the present inventionare formulated by mixing the Component (a) and the Component (b)together, in admixture with a pharmaceutical carrier for an immediate orextended release. An advantageous composition according to thisembodiment comprises an amount of granisetron hydrochloridecorresponding to from 0.5 mg to 2 mg of granisetron, as Component (a);and

-   -   from 10 mg to 20 mg, preferably from 15 mg to 20 mg, of        donepezil (as hydrochloride); or    -   from 6 mg to 18 mg, preferably from 9 mg to 18 mg, of        rivastigmine (as hydrogen tartrate); or    -   from 12 mg to 24 mg, preferably from 18 mg to 24 mg, of        galantamine (as hydrobromide),        as Component (b), wherein Components (a) and (b) are mixed        together and with a pharmaceutical carrier in an IR-formulation,        said composition being destined to be administered once or twice        per day.

According to another embodiment, the compositions of the presentinvention are formulated by mixing the Component (a) with apharmaceutical carrier for an immediate or extended release in tablets(Tablet A) and the Component (b), separately, with a pharmaceuticalcarrier for an immediate or extended release in tablets (Tablet B) andintroducing Tablet A and Tablet B in a capsule for oral administrationas described for example in GB 1204580 or in US 2007/0224259. Anadvantageous composition according to this embodiment consists of softor hard gelatin capsules each containing Tablet A comprising an amountof dolasetron mesylate hydrate equivalent to from 25 mg to 200 mg ofdolasetron, as Component (a), in admixture with a pharmaceutical carrierin a IR formulation; and

Tablet B, comprising

-   -   from 10 mg to 20 mg, preferably from 15 mg to 20 mg, of        donepezil (as hydrochloride); or    -   from 6 mg to 18 mg, preferably from 9 mg to 18 mg, of        rivastigmine (as hydrogen tartrate); or    -   from 12 mg to 24 mg, preferably from 18 mg to 24 mg, of        galantamine (as hydrobromide),        as Component (b), with a pharmaceutical carrier in an        IR-formulation, said composition being destined to be        administered once or twice per day.

According to a further embodiment, the compositions according to thepresent invention are formulated in a di-layer tablet which releases twodrug doses, in which the release of a drug from one drug-containinglayer does not interfere with the release of a drug from the otherdrug-containing layer as described for example in WO 2006/089493. Anadvantageous composition according to this embodiment consists of

Layer A, comprising an amount of ondansetron hydrochloride dihydrateequivalent to from 8 mg to 16 mg, preferably from 12 mg to 16 mg, ofondansetron, as Component (a), with a pharmaceutical carrier in a IRformulation and

Layer B, comprising 12 mg to 24 mg, preferably from 18 mg to 24 mg ofgalantamine (as hydrobromide),

as Component (b), in admixture with a pharmaceutical carrier in anIR-formulation, said composition being destined to be administered onceor twice per day.

According to another embodiment, the compositions of the presentinvention are formulated in oral disintegrable tablets. Particularlyadvantageous compositions according to this embodiment are orallydisintegrable tablets comprising

-   -   an amount of ondansetron hydrochloride dihydrate equivalent to        from 8 mg to 16 mg, preferably from 12 mg to 16 mg, of        ondansetron, as Component (a); and    -   from 10 mg to 20 mg, preferably from 15 mg to 20 mg, of        donepezil hydrochloride, as Component (b),        in admixture with a pharmaceutical carrier in an IR-formulation        for buccal mucosa absorption, said composition being destined to        be administered once or twice per day.

According to another embodiment, the compositions of the presentinvention are formulated in solutions for oral administration whereinComponent (a) and Component (b) are dissolved or suspended in water inadmixture with conventional carrier or vehicles. Particularlyadvantageous compositions according to this embodiment are oralsolutions or suspensions, each unit form thereof comprising

-   -   a Component (a) selected from the group consisting of        ondansetron (as hydrochloride dihydrate) in an amount of from 8        mg to 16 mg, preferably from 12 mg to 16 mg; domperidone (as        maleate) in an amount of from 10 mg to 20 mg, preferably from 15        mg to 20 mg; and metoclopramide (as hydrochloride monohydrate)        in an amount of 10 mg to 20 mg, preferably from 15 mg to 20 mg;        and    -   from 12 mg to 24 mg, preferably from 18 mg to 24 mg, of        galantamine (as hydrobromide), as Component (b),        in admixture with a pharmaceutical carrier in a liquid        IR-formulation for oral administration, said composition being        destined to be administered, in said dosage unit form, once or        twice per day.

According to another embodiment, the compositions of the presentinvention are formulated in patch for transdermal administration.Particularly advantageous compositions according to this embodiment aretransdermal patch formulations comprising

-   -   from 2 mg/24 hours to 6 mg/24 hours of granisetron (as        hydrochloride), as Component (a); and    -   from 10-15 mg/24 hours to 24 mg/24 hours of rivastigmine (as        hydrogen tartrate), as Component (b),        with a pharmaceutically acceptable carrier or diluent which is        suitable for systemic transdermal administration.

Another embodiment of the present invention provides units formsconsisting of tablets comprising

-   -   from 10 mg to 20 mg, preferably from 15 mg to 20 mg of        metoclopramide (as hydrochloride monohydrate), as Component (a);        and    -   from 12 mg to 24 mg, preferably from 18 mg to 24 mg, of        galantamine (as hydrobromide), as Component (b),        in admixture with a pharmaceutical carrier in a IR-formulation        for oral administration, said composition being destined to be        administered once or twice per day.

Another embodiment of the present invention provides units formsconsisting of tablets comprising

-   -   from 10 mg to 20 mg, preferably from 15 mg to 20 mg, of        domperidone (as maleate), as Component (a); and    -   from 6 mg to 18 mg, preferably from 9 mg to 18 mg, of        rivastigmine (as hydrogen tartrate), as Component (b),        in admixture with a pharmaceutical carrier in a IR-formulation        for oral administration, said composition being destined to be        administered once or twice per day.

A particularly advantageous embodiment of the present invention providesunits forms consisting of capsules comprising

-   -   from 40 mg to 250 mg, preferably from 80 mg to 250 mg, of        aprepitant, as Component (a); and    -   from 15 mg to 30 mg, preferably from 20 mg to 30 mg, of        donepezil (as hydrochloride), as Component (b),        in admixture with a pharmaceutical carrier in a IR-formulation        for oral administration, said composition being destined to be        administered once a day.

As compared to known drugs of the acetylcholine esterase inhibitor typenow used alone in the treatment of Alzheimer type dementias, the abovecombined pharmaceutical compositions show greater and longer efficacyand less adverse effects by allowing the safe and tolerableadministration of larger and thus more therapeutically effectivequantities of said acetylcholine esterase inhibitor. In particular, theacetylcholine esterase inhibitor of the pharmaceutical compositions ofthe present invention is safe and effective, alone or in combinationwith other pharmaceuticals, in treating patients in need of anacetylcholine esterase inhibition, in particular dementias of theAlzheimer type on a once or twice daily basis.

The pathologic conditions treated with the composition of the presentinvention include, but are not limited to, Alzheimer's disease,Parkinson's disease dementia, and other disorders of human cognitive andneurobehavioral function that are treated, in part, by pharmaceuticalsintended to augment brain acetylcholine-mediated neurotransmission.

The therapeutic efficacy is measured by the degree to which cognitiveand other neurobehavioral disabilities associated with dementias of theAlzheimer type, as documented by the use of standard scales, arereduced.

The following examples illustrate the invention.

Example 1 Orally Disintegrating Tablets Containing 15 mg of DonepezilHydrochloride and 4 mg of Ondansetron

One and a half kilogram of donepezil hydrochloride and 1.8 kg of cornstarch are mixed thoroughly until complete homogenizing of the mixturewhich, after a passage through a 35 mesh sieve, is added with apreviously prepared mixture of 400 g of ondansetron base, thoroughlystirred together with 2.4 kg of corn starch and sieved at 35 mesh. Themixture thus obtained is added with 0.6 kg of strawberry flavor powder,0.2 kg of sodium saccharin, 13.08 kg of lactose, 4.4 kg ofmicrocrystalline cellulose, and 2.9 kg of sorbitol. The mixture is mixeduntil complete homogenization, then it is added with 0.1 kg of magnesiumstearate, mixed again and compressed with punches of 7 mm to obtain100,000 orally disintegrating tablets having the following composition

Donepezil hydrochloride 15.00 mg Ondansetron 4.00 mg Corn starch 42.00mg Strawberry flavor powder 6.00 mg Sodium saccharin 2.00 mg Lactose130.00 mg Microcrystalline cellulose 44.00 mg Sorbitol 29.00 mgMagnesium stearate 1.00 mg

Example 2

Capsules for IR oral administration are prepared by mixing the followingingredients:

Ingredients Parts by weight Rivastigmine (as hydrogen tartrate) 900Domperidone (as maleate) 1,000 Lactose USP 7,350 Colloidal silicondioxide 50After mixing, the mixture is screened through a 40 mesh screen andintroduced in two-piece hard gelatin capsules No. 3, each containing 9mg of rivastigmine and 10 mg of domperidone.

Example 3

Tablets for IR oral administration containing 5 mg of donepezilhydrochloride formulated with a pharmaceutical carrier, tabletscontaining 10 mg of donepezil hydrochloride formulated with apharmaceutical carrier and tablets containing 10 mg of metoclopramideformulated with a pharmaceutical carrier are distributed in capsules asdescribed in GB 1,254,580, such that unit dosage forms containing 15 mgof donepezil hydrochloride and 10 mg of metoclopramide are prepared.

Example 4

The calculated amounts of metoclopramimide monohydrochloridemonohydrate, galantamine hydrobromide, methyl parahydroxybenzoate,propyl parahydroxybenzoate, sodium saccharin, sodium sorbate,hydroxymethylcellulose, propylene glycol, ethanol, mandarin oil, carameloil, custard oil, sodium hydroxide and purified water are mixed andformulated, according to conventional techniques, to prepare 100 ml ofan oral solution, containing 10 mg/ml of metoclopramide and 6 mg/ml ofgalantamine, for a IR administration, having the following composition

metoclopramide monohydrochloride monohydrate 105.000 mg galantaminehydrobromide 7.668 mg methyl p-hydroxybenzoate 80.000 mg propylp-hydroxybenzoate 20.000 mg sodium sorbate 100.000 mghydroxymethylcellulose 400.000 mg sodium saccharin 0.076 mg propyleneglycol 0.500 ml ethanol 1.000 ml mandarin oil 0.400 ml caramel oil 0.500ml custard oil 0.010 ml sodium hydroxide to pH 3.0 purified water to100.000 ml

Example 5

The calculated amounts of galantamine hydrobromide, metoclopramimidemonohydrochloride monohydrate, guar gum, methyl cellulose, ethylcellulose, silica gel, potato starch, sorbitol and pentaerytritol aremixed and formulated, according to conventional techniques, to prepare150-mg IR-tablets having the following composition

Galantamine hydrobromide 23.06 mg Metoclopramide monohydrochloridemonohydrate 10.50 mg Guar gum 2.00 mg Methylcellulose 2.00 mgEthylcellulose 2.00 mg Silica gel 3.00 mg Potato starch 5.00 mg Sorbitol2.44 mg Pentaerythritol 97.00 mg

The invention claimed is:
 1. A method for treating a patient sufferingfrom an Alzheimer type dementia, which comprises administering to saidpatient an acetyl choline esterase inhibitor (AChEI) selected from thegroup consisting of tacrine, donepezil, rivastigmine, galantamine, andpharmaceutically acceptable salts thereof, in combination with anon-anticholinergic antiemetic agent, said AChEI being administered tosaid patient at a dose level from 1.1 to 4 times greater than arecommended maximal dose level approved by the U.S. FDA.
 2. The methodof claim 1, wherein said non-anticholinergic antiemetic agent isselected from the group consisting of the following anticholinergicantiemetic agent: 5-HT3 receptor antagonists, dopamine antagonists, H1histamine receptor antagonists, NK1 receptor antagonists and cannabinoidagonists.
 3. The method of claim 2, wherein said 5-HT3 receptorantagonist is selected from group consisting of ondansetron, thepharmaceutically acceptable salts and solvates of ondansetron,granisetron, the pharmaceutically acceptable salts and solvates ofgranisetron, tropisetron, the pharmaceutically acceptable salts andsolvates of tropisetron, lerisetron, the pharmaceutically acceptablesalts and solvates of lerisetron, ramosetron and the pharmaceuticallyacceptable salts and solvates of ramosetron.
 4. The method of claim 2,wherein said dopamine antagonist is selected from group consisting ofdomperidone, the pharmaceutically acceptable salts and solvates ofdomperidone, metoclopramide, the pharmaceutically acceptable salts andsolvates of metoclopramide, bromopride, the pharmaceutically acceptablesalts of bromopride, clebopride, the pharmaceutically acceptable saltsof clebopride, alizapride and the pharmaceutically acceptable salts ofalizapride.
 5. The method of claim 2, wherein said HI histamine receptorantagonist is meclizine or a pharmaceutically acceptable salt or solvatethereof.
 6. The method of claim 2, wherein said cannabinoid agonist isdronabinol or nabilone.
 7. The method of claim 2, wherein said NK1receptor antagonist is aprepitant or casopitant.
 8. The method of claim1 wherein said AChEI is selected from the group consisting of donepezil,rivastigmine, galantamine, and pharmaceutically acceptable saltsthereof.
 9. The method of claim 1, wherein said non-anticholinergicantiemetic agent is a 5-HT3-receptor antagonist; and said AChEI isselected from the group consisting of donepezil and pharmaceuticallyacceptable salts thereof.
 10. The method of claim 9, wherein said5-HT3-receptor antagonist is selected from the group consisting ofondansetron, the pharmaceutically acceptable salts and solvates ofondansetron, granisetron, the pharmaceutically acceptable salts andsolvates of granisetron, tropisetron, the pharmaceutically acceptablesalts and solvates of tropisetron, lerisetron, the pharmaceuticallyacceptable salts and solvates of lerisetron, ramosetron and thepharmaceutically acceptable salts and solvates of ramosetron.
 11. Amethod for treating a patient suffering from an Alzheimer type dementia,which comprises administering to said patient an acetyl choline esteraseinhibitor (AChEI) selected from the group consisting of donepezil andpharmaceutically acceptable salts thereof, in combination with anon-anticholinergic antiemetic agent consisting of a 5-HT3 receptorantagonist selected from the group consisting of granisetron andpharmaceutically acceptable salts and solvates thereof, said AChEI beingadministered to said patient at a dose level from 1.1 to 4 times greaterthan a recommended maximal dose level approved by the U.S. FDA.
 12. Themethod of claim 11, wherein said 5-HT3 receptor antagonist isadministered at a daily dose, in granisetron, of from 1 mg to 6 mg. 13.The method of claim 11, wherein said AChEI is administered orally orparenterally.
 14. The method of claim 12, wherein said combination isorally administered in an IR dosage unit form comprising from 0.5 mg to3 mg of said 5-HT3 receptor antagonist and from 15 mg to 30 mg of saidAChEI, in admixture with a pharmaceutical carrier.